This Program examines the interaction of proliferation and cortical interneuron fate determination and probes the functional consequences of altering interneuron subpopulations. Generating the correct number and subtypes of these neurons is crucial for the development of a normally functioning brain, and Project 2 focuses on the interacting roles of several signaling systems, Notch, Wnt, and Sonic hedgehog (Shh), that critically influence this process. Aim 1. Notch signaling regulates proliferation and cell fate in many organs, but a role for Notch in interneuron generation by the medial ganglionic eminence (MGE), the source of critical cortical interneuron subpopulations, is not known. We identified the Notch ligand Jagged-1 in a microarray screen for genes differentially expressed in the dorsal versus the ventral MGE, raising the possibility that Notch signaling regulates interneuron fate determination. In Aim 1, we examine conditional loss of Jagged-1 function in the dorsal MGE. Via interactions with Project 1, we explore abnormalities of cyclin D2 expression that we have identified in preliminary studies with these mutants. Via interactions with Project 3, we will further explore Notch-related alterations in proliferative behavior using live imaging in organotypic slice cultures. Aim 2. During the first four years of this Program we have shown that the expression of the interneuron fate-determining transcription factor, Nkx2.1, requires Shh signaling during interneuron genesis. We also found that proliferation of Nkx2.1-expressing, MGE progenitors requires canonical Wnt signaling. In the other systems, Shh signaling can be necessary for the expression of Tcf4, an effector of canonical Wnt signaling, that we have shown to be expressed in the subcortical telencephalon. Tcf4, in turn, has been shown to activate the expression of Jagged 1 in non-neural tissue. In Aim 2 we examine potential interactions of Shh, Wnt, and Notch signaling effectors as they relate to MGE proliferation and interneuron fate. Again, interaction with Projects 1 & 3 will be critical for teasing out the mechanisms underlying defects in cell cycle and modes of progenitor division that are generated through our various signaling manipulations. As effectors of all three of these signaling systems, like cortical interneurons themselves, are associated with neurological and neuropsychiatric disease, Project 2 will generate several novel mouse models of selective cortical interneuron losses, one of which is expected to produce an inducible, titratable, and time-limited reduction of interneuron genesis, for detailed investigation by the Neurobehavioral Analysis Core. The overarching goal of this project is to link critical mechanisms in neurogenesis and neural subtype fate with clinically germane aspects of brain function.